Introduction

Hantaviruses are a genus of single-stranded, negative sense RNA viruses in the family Bunyaviridae. It normally infects rodents. Hantavirus causes pulmonary syndrome (HVPS) in the Americas and causes hemorrhagic fever with renal syndrome (HFRS) in other parts of the world, notably Europe and East Asia (China, Russia, and Korea).

Hantaan is a river in Korea where the first virus in this genus was identified in 1976. This virus caused Korean hemorrhagic fever in the American troops who fought the Korean war in the 1950s. The first outbreak on US soil was reported from the four-corner region amongst the native Indian tribes in 1993. In this four-corner southwest region of the United States, Arizona, New Mexico, Colorado, and Utah come together. The first patient was a woman, who presented with acute onset of dyspnea and was found to have bilateral diffuse infiltrates. Her autopsy showed that the lungs were twice the weight of normal lungs for her age. During the evaluation of the outbreak, all victims were found to have exposure to deer mice. There was no person-to-person transmission during this outbreak. The health care workers who resuscitated these patients did not get infected. The American species of hantavirus, which caused the outbreak at four-corner regions was eventually named Sin Nombre hantavirus.[1][2][3]

Etiology

Hantaviruses are enveloped RNA viruses measuring 80 nm to 120 nm. The genome is divided into three segments. The large (L) segment coding for viral transcriptase, the medium (M) segment coding for glycoproteins of the capsule and the small (S) segment coding for the protein of the viral nucleocapsid.

There are several species of hantavirus causing hantavirus pulmonary syndrome (HPS) also known as hantavirus cardiopulmonary syndrome (HCPS). The host for Sin Nombre hantavirus is the deer rat (Peromyscus maniculatus) found in rural regions along the Mississippi river. The New York virus is associated with the white footed mouse (Peromyscus leucopus). The other hantaviruses are the Black Creek Canal virus, the Bayou virus with the main host being wild rats from the Muridae family.[4][5][6]

Epidemiology

Since 1995, hantavirus pulmonary syndrome is a reportable disease, and in 2015 the hantavirus non-pulmonary disease was made reportable as well. In the United States, most cases have occurred west of the Mississippi River, but overall 36 states have reported hantavirus pulmonary syndrome cases. In 2001, there were 255 cases reported by the United States. Brazil has the highest number of cases. The cases from South America outnumber the North American cases. The countries with most cases are Brazil, Argentina, and Chile.[7]

In the United States, most cases of hantavirus infection have occurred as outbreaks, the most recent being at the Yosemite National Park amongst the park visitors during July to August of 2012.

Transmission occurs by exposure to aerosolized dried feces and urine from rodents of Muridae family, which are the main reservoir in nature.

Person-to-person transmission has been recorded in the outbreak in Argentina due to Andes virus in 1996. The health care workers including five physicians got infected during the Andes virus outbreak. A review of cases with well-defined exposures from the registry suggests that the incubation period of hantavirus pulmonary syndrome is 9 to 33 days (median 14 to 17 days). Such person-to-person transmission has not been reported with Sin Nombre or other species of Hanta viruses.

Worldwide, hantaviruses infect about 30,000 humans per year and cause hemorrhagic fever with renal syndrome (HFRS).[8]

Pathophysiology

There is no ideal model to study hantavirus infection leading to hantavirus pulmonary syndrome. In a recently described rhesus macaque model, the Sin Nombre virus causes a hantavirus pulmonary syndrome-like illness characterized by low platelets, leukocytosis, and rapid onset of respiratory distress due to interstitial pneumonia. The first clinical features of infection in this model were a cough, tachypnea, and respiratory crackles. The earliest onset of symptoms occurred at day six, but the overall range was 14 to 16 days. Within 72 hours of the onset of respiratory symptoms, there was an acute respiratory failure with severe multilobar pulmonary infiltrates right ventricular enlargement, and pleural effusion due to heart failure. Nasal, oral, and rectal swabs were consistently negative for the viral RNA even at the peak infection. This suggests that unlike the Andes species, the Sin Nombre virus is not transmissible from person-to-person. While the swabs for negative, viremia was demonstrated in the infected models prior to the onset of the respiratory symptoms by an average of two days.

The virus caused a predominantly pro-inflammatory cytokine (Th1/Th2 cytokines, IFN-g, IL-1beta, IL-6, IL-18, and IL-13) release in the macaque models and noted at about 12 days post infection. The anti-inflammatory cytokine release (IL-1 receptor antagonist, IL-15, and GM-CSF) occurred only when the respiratory symptoms were present. Neutrophilia with left shift was present in the infected model, which is like hantavirus pulmonary syndrome infection in humans. In humans, neutrophilia with left shift supports the diagnosis of hantavirus pulmonary syndrome. Interestingly one may see a mixed pattern (viral and bacterial) on complete blood count (CBC) with increased atypical lymphocytes and increased bands, and overall normal white blood cells (WBC). Polymorphonuclear cells may or may not be elevated.

There was no elevated D-dimers in the macaque models. In human infection, however, prothrombin time is usually normal; studies in human infections have shown that the tissue plasminogen activator (tPA) is elevated.

Host response: Immunoglobulin M (IgM) is produced by the host at first followed by immunoglobulin G (IgG) antibodies. Immunoglobulins E (IgE) antibodies are also found and notably, contribute to the host defense against the Hanta virus infection.

The immune complexes coat the red blood cells and the platelets. Thrombocytopenia is frequently noted on CBC in human hantavirus pulmonary syndrome infections.

Tests for liver injury become abnormal late in the disease and reflect end stage in the natural history of the disease.

While there was a diffuse endothelial infection of a variety of tested in this model organs (heart, kidney, spleen, and liver), the cytokine responses were predominantly in the lungs which is suggestive of compartmentalization of the immune response noted in human hantavirus pulmonary syndrome. The hantaviruses are capable of preferentially entering the endothelial cells, and immunohistochemistry studies demonstrate hanta virus nucleic acids in the pulmonary endothelial cells and the macrophages. Recently decay accelerating factor, and CD55 receptors on the endothelial cells have been identified as co-factors required for attachment and entry of the hanta viruses into the human endothelial cells. Differences in co-factors may explain the different clinical manifestations (hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome of the hantaviruses). Hanta viruses are capable of multiplying in the endothelial cells without causing visible cytopathic effect and injury in in-vitro models.

There is a functional impairment of the vascular endothelium with capillary dilation. The direct mechanism for vascular endothelial injury needs further elucidation.

Histopathology

In early stages, lung histology shows multifocal thickened alveolar septae with edema, macrophages, fibrin, and few neutrophils. There is very little cellular debris, thick membranes, and few type II reparative pneumocytes. The type I pneumocyte processes are intact in the early phase, and there is a minimal external injury to the endothelium. This is different from the histological findings of diffuse alveolar damage, where there is extensive cellular debris, destruction of type 1 pneumocytes, prominent neutrophilic infiltrate with fibrosing alveolitis.

In late stages, or in survivors, the histology is like that of exudative and proliferative phases of diffuse alveolar damage. There is a distortion of the lung architecture and proliferation of reparative type 2 pneumocytes.

Vascular changes are also seen in other organs notably spleen. In liver, there is scattered coagulative necrosis. There is no single pathognomonic feature on histology. Early histological features of lung tissue obtained by biopsy may give a clue but are seldom obtained in clinical practice.

History and Physical

Eliciting a detail exposure history is critical. Activities that raise dust and have the potential to aerosolize rodent droppings, saliva, or feces can lead to inhalation of the virus particles, which descend into the lower lobes and set up the infection. Healthy and immunocompetent patients can get infected as well. There is no prior history of upper respiratory tract infection.

There are five clinical stages or phases of the hantavirus infection causing the hepatopulmonary syndrome. The incubation phase (4 to 33 days); the febrile phase, the cardiopulmonary phase, the diuretic phase, and the convalescent phase. The onset of fever is abrupt and associated with flu-like symptoms and erythematous rash. A cough heralds the onset of cardiopulmonary phase. This phase occurs about three days after the febrile phase. There is hypotension, respiratory failure, and oliguria during this phase. Petechial rash is also noted. Most deaths occur during this cardiopulmonary phase. The rapid progression of the febrile, flu-like illness to severe cardiopulmonary failure is one of the characteristics of the hepatopulmonary syndrome.

If the patient survives for two weeks or more, the diuretic phase sets in. The patient is relatively hypervolemic during this period. The convalescent phase begins late and may require up to four months. Due to frequent fluid shifts, the electrolyte abnormalities are frequent through phases two to four.

The differential diagnosis should include conditions causing fever with rash, fever with thrombocytopenia such as dengue, fever with atypical pneumonia, gram-negative sepsis, and acute respiratory distress syndrome (ARDS).

Evaluation

Abnormalities are noted in complete blood count (CBC) as well as in chemistry due to fluid electrolyte imbalances. Interestingly the CBC picture may have left shift with and without neutrophilia, which is more typical of bacterial infections, atypical lymphocytosis is present suggesting a viral etiology. There is thrombocytopenia in the prodromal phase, which also supports the diagnosis of hepatopulmonary syndrome. Generally, the prothrombin time is within normal limits.[9][10]

Serology is the most common approach to confirm hanta virus infections. These tests are indirect IgG and IgM ELISAs, and M antibody-capture ELISA. Hantavirus specific immunoglobulin M (IgM) is detected early in the disease. Documenting rising titers of hantavirus-specific immunoglobulin G (IgG) is another method to make the diagnosis. These are ELISA tests, which are used by Centers for Disease Control and Prevention (CDC) as well. The IgM antibodies last for months after hanta virus infection. Serological tests do not distinguish between various types of hanta viruses.

Immunoblot and neutralization tests have also been used to diagnose hanta virus infections. These tests are cumbersome to perform and do not differentiate between various hanta virus species.

There is a clear need for a rapid test in this disease due to its rapid and predictable progression once the febrile phase sets in. A one-hour enzyme immune assay has been developed. There are a variety of rapid tests each identifying specific species of hantavirus. Sensitivities of most of these rapid tests are in the range of 96% to 100%.

Molecular tests are highly specific (100%) and sensitive (94%). The polymerase chain reaction (PCR) tests detect other related species of hanta viruses, which may cause hepatopulmonary syndrome or hemorrhagic fever with renal syndrome such as Puumala virus or Dobrava viruses. PCR tests can be done on clinical specimens obtained from biopsy. The Sin Nombre virus is not shed in the stool, urine or saliva so swabs from these regions may not detect the virus. Hantavirus antigen can be detected by immunohistochemistry in a clinical specimen such as blood and tissue. The real time PCR (RT-PCR) tests allow for quantitative detection of the viral antigens using the S segment of the viral genome.

Overall, using molecular tests and antigen detection tests is superior in the early phases of the disease. Since IgM lingers for months, tests detecting IgM-specific antibodies can be employed in the convalescent phase of the illness.

Therefore, a combination of serologic testing (ELISA) with molecular testing (RT-PCR) appears to be optimal approach at present.

The imaging in the febrile phase shows interstitial edema, and the physical exam during this phase may reveal crackles on auscultation of the lungs. The interstitial pattern changes rapidly to multi lobar, bilateral alveolar space disease. The alveolar space disease is more central or in the lower lobes and therefore unlike the peripheral infiltrates in acute respiratory distress syndrome (ARDS). ARDS does not have a preceding interstitial pattern of infiltrates and the alveolar disease pattern is peripheral.

Treatment / Management

There is no antiviral therapy approved for treating hantavirus infection. Supportive care is the mainstay of therapy. Early admission to intensive care unit is warranted as the disease is likely to progress. Consider early intubation and oxygen supplementation to conserve physiological reserves during the period of respiratory support. While hantavirus infection is systemic and viral nucleic acid is found in other organs on immunohistochemistry, the clinical picture is dominated by the pathology in the lung. Due to rapid fluid shifts, close attention must be paid to the fluid and electrolyte balance in intensive care units. [11]

The mortality in severe cases with evidence of bilateral infiltrates on chest x-ray (CXR) is high, in the range of 30% to 50%. Mild cases are not fatal. After the onset of febrile phase, if the disease does not progress rapidly to the cardiopulmonary phase within in three to five days than it is unlikely to progress afterward. In these cases, the outcome is considerably better, and death is unlikely.

Pearls and Other Issues

Rodent control in and around human living quarters is the primary method of prevention of hantavirus infection. There are no recommendations restricting travel.

Enhancing Healthcare Team Outcomes

Hantavirus cardiopulmonary syndrome is a lethal illness and best managed by a multidisciplinary team that includes ICU nurses. There is no specific treatment for the infection and aggressive support and mechanical ventilation is required in most patients. Even with optimal therapy, the death rate exceeds 40%. Those patients who maintain a clear chest x-ray tend to have a good outcome.

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Take a quiz of the questions on this article.

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

A patient presents with gradual onset of tachypnea, fever, and tachycardia. He has significant respiratory distress. A blood smear reveals marked leukocytosis with an appearance of immunoblasts, which exceed 10% of the total. A chest x-ray reveals bilateral fluffy infiltrates. Which organism most likely is the cause of this presentation?

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

A 48-year-old man living in a rural area of the Rocky Mountains presents with a 2-week history of feeling unwell. Initially, he had a headache, malaise, fever, and muscle pain. Last week, he developed dyspnea and a dry cough. He was brought in by emergency medical services (EMS) because of shock and oliguria. On physical exam, he is ill-looking and struggling to breathe. The patient is quickly intubated and transferred to the intensive care unit. By now he has a generalized skin rash with purpura. Blood work reveals leukocytosis, and a smear shows atypical lymphocytes with immunoblasts. There is dysfunction of the liver and kidneys, and a disseminated intravascular coagulopathy (DIC) picture is evident. A chest x-ray shows pulmonary edema without enlargement of the cardiac silhouette. The infectious disease consultant suspects that the patient may have a deadly infection. Which of the following organisms can present with the above features?

Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of CNS-Public Community Health. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for CNS-Public Community Health, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in CNS-Public Community Health, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of CNS-Public Community Health. When it is time for the CNS-Public Community Health board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study CNS-Public Community Health.